Obesity is an important risk factor for asthma. We propose to investigate the mechanistic basis for this relationship. Our data indicate that airway responsiveness is increased in obese mice and that obese mice have increased responses to common asthma triggers. Serum levels of adiponectin are reduced in obesity, and our data indicate that exogenous adiponectin attenuates the airway inflammation and hyperresponsiveness associated with ovalbumin sensitization and airway challenge in mice. Our data also show that ovalbumin challenge reduces serum adiponectin and lung adiponectin receptor expression. Moreover, airway smooth muscle (ASM) cells express adiponectin receptors and respond to adiponectin with changes in cell function. Based on these data we hypothesize that adiponectin has both anti-inflammatory effects and direct effects on ASM, which act to attenuate the asthmatic diathesis and that obesity-related decreases in serum adiponectin reduce the protective effects of this hormone. To address this hypothesis, we will measure airway responsiveness, airway inflammation, serum adiponectin, adipose tissue adiponectin mRNA expression, and lung adiponectin receptor expression in wild type mice, mice deficient in adiponectin, and mice deficient in T-cadherin, the receptor for the high molecular weight form of adiponectin, following exposure to ozone or allergen. We will also determine whether exogenous adiponectin can reverse the innate airway hyperresponsiveness and the increased responses to allergen and ozone observed in obese mice. Since ASM is a key effector cell in asthma, and since ASM cells express adiponectin receptors, we will also examine the dose related effects of adiponectin on murine ASM cells. Outcomes will include: 1) cell proliferation; 2) inflammatory gene expression; and 3) ASM mechanics and remodeling. Since in other cell types, the effects of adiponectin are mediated via AMP kinase (AMPK) activation, we will examine the role of AMPK in the effects of adiponectin on ASM using AMPK activators and chemical or molecular inhibition of AMPK. Demonstrating the role and mechanism of action of adiponectin in these models could directly and quickly impact the treatment of obesity-related asthma. Lay Summary: Obesity is an important risk factor for asthma. The goal of this research project is to try and understand how obesity causes or worsens asthma. The focus of our research is a hormone produced by fat cells. Understanding the relationship between obesity and asthma could lead to new strategies for treating asthma, particularly in patients who are overweight or obese. [unreadable] [unreadable] [unreadable]